Medications and other pharmaceutical products have traditionally been administered in doses via oral ingestion, nasal sprays or injections. These delivery methods are not always effective for patients needing a prolonged and constant supply of an active ingredient delivered to the bloodstream, for example if the treating agent is particularly sensitive to moisture, pH, or enzymes. As used herein, with regard to treating agents, the term “sensitive” to moisture, pH, or enzymes means a treating agent that is metabolized or otherwise degraded when exposed to moisture, pH or enzymes such as upon administration to a body cavity. Depending on the degree of sensitivity for a particular treating agent, the length of time and the degree of exposure (for example, the amount of water present) will determine whether a significant amount of the treating agent is metabolized or degraded. The particular degree of sensitivity for each treating agent should also be kept in mind during manufacture. During manufacture, sensitivity to enzymes is normally not an issue, but moisture or even pH during manufacture can be a problem for certain treating agents. A treating agents' sensitivity to moisture or pH determines the time and degree of contact that a particular treating agent may have with moisture or an adverse pH during the manufacturing process, without undergoing substantial degradation. Therefore, the method of manufacture should take into account the particular treating agents' degree of sensitivity.
Particularly difficult delivery schedules are those that require dosing during sleep time hours. For these patients, intravenous (“IV”) lines, slow-dissolving pills, and suppositories or transdermal patches have been prescribed. However, the inconvenience and discomfort of IVs, the short life span of many ingested active ingredients from gastrointestinal degradation or first-pass liver metabolism, and the inability of many products to be comfortably delivered transdermally in suitable doses or in controlled concentrations have proven these methods frequently unsatisfactory.
Previous artisans have attempted to meet the needs of the art by developing products for the transmucosal administration of active ingredients. For example, certain active ingredients can be administered quickly into the bloodstream via the walls of a body cavity, such as the buccal or vaginal cavities, without the risk of first pass hepatic degradation. Generally, delivery of active ingredients through mucosal surfaces may be enhanced by the use of bioadhesive formulations. However, one particular area where those in the art have attempted, but heretofore failed, to meet the needs of the art is in developing a bioadhesive tablet useful for sustained release applications without risking degradation of the active ingredient before it is absorbed.
“Sustained release” generally refers to continuous or sporadic release of an active ingredient over an extended time after a single administration, whereby the level of active ingredient available to the host patient over a period of time. “Controlled release” is a different issue. A drug could be released over 72 hours, but hour-to-hour variation in the rate of release could be random, for example 600% or more. Such a formulation would be characterized as sustained but not controlled release (unless the pattern of release was intentional rather than random). “Controlled release” is not sporadic, but a constant or ordered release of the drug over time. For example, the release can often be maintained at some constant level over time or alternatively the release of the active ingredient could be controlled over a period of time wherein the level of active ingredient available to the host (bioavailability) may intentionally be at a variable but predetermined level at a particular instant in time of treatment, for example in an effort to mimic natural fluctuations in level.
The sustained release bioadhesive tablets known in the art can be generally broken down into two categories: (1) tablets consisting of water soluble carbomers, and (2) tablets consisting of insoluble polymers. Both types of tablets have proven unsatisfactory for many applications. For example, numerous artisans have attempted to formulate a suitable sustained release bioadhesive tablet from water soluble carbomers, such as carbomer 934P or CARBOPOL™ 974 resin (commercially available from B.F. Goodrich, Cleveland, Ohio). However, such tablets often are only able to adhere to the wall of a body cavity for short periods of time, e.g., six hours or less. Also, these tablets are easily dislodged from the wall of a body cavity and thus place patients using such tablets buccally at risk of asphyxiation. Furthermore, these prior art tablets inherently become hydrated relatively quickly and thus may prematurely expose the reservoir of active ingredient to degradation by moisture or by enzymes from the host environment such as from bacteria in the septic oral or vaginal cavities.
Similarly, tablets comprised of insoluble polymers, such as polycarbophil, have proven unsuitable for many applications. For example, although polycarbophil-containing tablets are capable of prolonged attachment to the wall of a body cavity, such tablets do not adhere immediately, making them impractical for certain treatments such a buccal delivery of active ingredients to patients during sleep time hours. Further, such tablets often do not soften sufficiently to provide comfort and imperceptibility, or provide safety from potential aspiration of the tablet.
Furthermore, for example, neither type of prior art tablet is particularly suitable for treating many conditions. As alluded to previously, there are numerous medical conditions in which a sustained and/or controlled release of active ingredient(s) is desired for any of numerous reasons including, for example, to alleviate the impact of first-pass hepatic metabolism of the active ingredient or the risk of premature degradation of the active ingredient by moisture, pH effects, or enzymes, or to attain the comfort and convenience offered by a suitable bioadhesive tablet. Such conditions include, but are not limited to, for example, those needing treatment with an active ingredient that may be, but is not limited to, a glycoprotein, protein, sex hormone, anti-hormone, nitrate, beta-agonist, beta-antagonist, opioid, opioid-antagonist, antidepressant, HMG CoA (3-hydroxy-3-methylglutaryl Coenzyme A) reductase inhibitor, antihistamine, ACE (angiotensin converting enzyme) inhibitor, and/or prostaglandin. Heretofore the art has required such patients to undergo the more invasive and less suitable techniques and methods of delivery described above.
To illustrate the need in the art, consider hypogonadal men, for example. Hypogonadism in man is characterized by a deficiency or absence of endogenous testosterone production. Abnormally low levels of testosterone may place men at risk of “Andropause”, wherein men are at greater risk of cardiovascular disease, Alzheimer's disease, and osteoporosis.
Testosterone has traditionally been used to treat hypogonadal men. However, to be most effective, the treatment must be capable of complete physiologic testosterone replacement. Moreover, the treatment must be capable of providing sustained levels of testosterone through the night. Preferably, the treatment provides physiologic levels with circadian delivery of testosterone, with lower levels released during the night and peak levels occurring during the early morning. Transdermal testosterone patches typically produce only sub-physiologic levels and thus incomplete relief. Similarly, the prior art buccal tablets heretofore described would be ineffective or impractical for such sustained testosterone delivery.
The hormone testosterone, like many other drugs, including many other proteins and glycoproteins, undergoes high first pass hepatic metabolism. Accordingly, as will be appreciated by one of ordinary skill in the art, buccal or vaginal tablets consisting of materials that are incapable of keeping the interior reservoir of the tablet in the dry state for prolonged periods are inherently incapable of preventing dissolution and swallowing, or of preventing dissolution and rapid absorption of the active ingredient through the mucosa. Furthermore, as will be appreciated by one of ordinary skill in the art, tablets which are unable to quickly adhere to the target area or are able to become dislodged are especially impractical for treatments which use night-time delivery, such as testosterone treatment.
Active ingredients such as testosterone may also undergo undesired metabolism. For example, 5α-reductase converts testosterone to 5α-dihydrotesterone (DHT). DHT may cause adverse effects such as hair loss and prostate disorders. Similarly, 5α-reductase may metabolize other active ingredients such as progesterone.
Various testosterone formulations have been developed to circumvent the problems inherent in rapid clearance of orally and parenterally administered agents. These include transdermal preparations, pellets for subcutaneous implantation, biodegradable microcapsule formulations for injection, and inclusion complexes that enhance sublingual absorption of the hormone. Of these, the transdermalskin patches and gel products are probably the most widely used. Under optimal conditions, they are intended to approximate the physiological pattern of hormone levels throughout the day and provide an alternative to parenteral therapy.
However, the scrotal preparation causes a disproportionate increase in plasma dihydrotestosterone (DHT) to a level that is 30 to 40% that of testosterone, presumably because of the high level of 5α-reductase in scrotal skin. Other skin patches likewise produce high levels of DHT. Such increases in serum DHT have also been reported after treatment with the extremely long-acting parenteral testosterone ester testosterone buciclate and with the oral ester testosterone undecanoate. Williams Textbook of Endocrinology, 9th Ed., W. B. Saunders Company, p. 853. Thus, the present invention advantageously avoids the side effects that may be caused by 5α-reductase's metabolism of active ingredients.
Furthermore, as will be appreciated by one of ordinary skill in the art, the advantages of a sustained release, bioadhesive tablet according to the present invention are useful for much more than the treatment of hypogonadism in men. For example, patients often require sustained release hormone treatment for various conditions. In addition, other medications, such as steroids for treating such conditions as asthma, involve treatments where desired peak levels are at night during sleep-time hours. Accordingly, one of ordinary skill in the art will appreciate that there exists a long-felt, yet unresolved, need to develop a bioadhesive, sustained release tablet to satisfy the aforementioned needs of the art, including, but not limited to, the delivery of therapeutically effective amounts of an active ingredient which may be metabolized or otherwise degraded by moisture, enzymes, or pH effects, such as, for example, glycoproteins, proteins, sex hormones, anti-hormones, nitrates, beta-agonists, beta-antagonists, opioids, opioid-antagonists antidepressants, HMG CoA reductase inhibitors, antihistamines, ACE inhibitors, and/or prostaglandins.
For example, an advantage to administering treating agents such as terbutaline (especially for sleep time administration) through a sustained release bioadhesive tablet according to the instant invention is that such administration provides controlled, extended release to help prevent high peak blood serum levels of the terbutaline. This is particularly useful when the treating agent, such as terbutaline, is associated with adverse side effects at high blood serum levels.